Mutations in the gene ATP1A3 affect the neuron-specific major ion transporter in the brain, the sodium pump or, Na,K-ATPase. This causes rare diseases, Alternating Hemiplegia of Childhood (AHC) and Rapid-Onset Dystonia-Parkinsonism (RDP). Mutations occur in families with dominant inheritance, and there are many de novo mutations occurring in ~100 different places in the gene to date. The objectives of this application are to apply a highly multi-disciplinary, collaborative approach to determine the full range of clinical phenotypes; develop a brain imaging biomarker; and investigate the underlying functionality of the mutations. The full range of clinical phenotypes includes motor, cognitive, developmental, and psychiatric symptoms, and is predicted to expand with a screen to discover patients with new ATP1A3 mutations and features intermediate between AHC and RDP. The full range of phenotypes expressed in adult AHC patients is predicted to overlap with RDP patients and call for a shared approach to therapy development. An advanced brain imaging analysis is hypothesized to lead to a signature of structural and functional features that can be used for three parallel purposes: to identify the specific brain pathways that are impacted and that result in the clinical symptoms, to augment the tools available for future clinical trials, and to potentilly enhance the on-going care of patients by making it possible to evaluate changes over time. The identification of pathways will assist in the future design of treatments, such as deep-brain stimulation. The potential for longitudinal study is particularly relevant because RDP patients, and we think also AHC patients, can have step-wise deterioration, often associated with stressful triggers. The third component, investigation of mutation mechanisms at the biochemical and cell biological level, is needed to determine if specific kinds of mutations result in different phenotypes, and why. This will contribute to rational design of therapies. This is an example of how the study of rare mutations can lead to advances in understanding brain connectivity (imaging) and its relationship to health (clinical phenotypes) and fundamental science (mutation mechanisms). The aims are: 1) Define the phenotypes for ATP1A3 mutation in adult patients including in-depth evaluation of adult AHC patients as well as returning and new RDP patients. Screen for a missing patient population between AHC and RDP; 2) Use advanced imaging methodology to assess alterations of specific brain pathways (correlating with RDP neuropathology) in adult AHC and RDP patients, and initiate longitudinal studies with returning patients; 3) Test the hypothesis that mutations with different enzymatic or cellular consequences will relate to clinical phenotypes and imaging findings, using in vitro mutagenesis and expression in human cell cultures.